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1.  Prevalence of periodontal pathogens in coronary atherosclerotic plaque of patients undergoing coronary artery bypass graft surgery 
Chronic bacterial infections have been associated with an increased risk for atherosclerosis and coronary artery disease. The ability of oral pathogens to colonize in coronary atheromatous plaque is well known. The aim of our study was to detect the presence of four common periodontal pathogens in coronary plaques. We detected the presence of 16S rRNA of Treponema denticola, Eikenella Corrodens, Porphyromonas gingivalis and Campylobacter rectus in subgingival and atherosclerotic plaques of CABG surgery by using Polymerase Chain Reaction.
51 patients in the age group of 40 to 80 years with chronic periodontitis were recruited for the study. These patients were suffering from Coronary Artery Disease (CAD) and underwent Coronary Artery Bypass Grafting (CABG). DNA was extracted from the subgingival plaque and coronary atheromatous plaque samples. Universal Primer for the general detection of bacterial DNA and the primers for T.denticola, E. Corrodens, C.rectus and P.gingivalis were used to amplify part of 16SrRNA gene by Polymerase Chain Reaction.
T.denticola, E.corrodens, C.rectus and P.gingivalis were detected in 49.01 %, 27.45 %, 21.51% and 45.10% of atherosclerotic plaque samples. In both subgingival and coronary plaque samples, T. denticola was detected in 39.21% of the cases, E.corrodens in 19.60%, C.rectus in 11.76% and P.gingivalis in 39.22% of the cases respectively.
Our study revealed the presence of significant bacterial DNA of oral pathogens in coronary plaques. This suggests possible relationship between periodontal infection and atherosclerosis and can help devise preventive treatment strategies.
PMCID: PMC3453943  PMID: 23139486
Atherosclerosis; Periodontal diseases; Periodontal pathogens; Inflammation and atherosclerosis; Polymerase chain reaction
2.  Factor VLeiden and Prothrombin G20210A Gene Polymorphisms in Patients with Coronary Artery Disease 
Yonsei Medical Journal  2008;49(2):237-243.
The precise molecular mechanisms culminating in coronary artery disease (CAD) are not well understood, despite a wealth of knowledge on predisposing risk factors and pathomechanisms. CAD and myocardial infarction (MI) are complex genetic diseases; neither the environment alone, nor a single gene, cause disease, rather, a mix of environmental and genetic factors lead to atherosclerosis of the coronary arteries.
Materials and Methods
In the present study, our aim was to investigate the roles of prothrombin G20210A mutation and Factor VLeiden mutation in atherosclerotic coronary artery disease. 287 subjects (106 control subjects, who were angiographically normal, and 181 angiographically documented coronary atherosclerotic patients who exhibited coronary artery narrowing to a degree of ≥ 50%) were included in this study. The mutations were assessed with LightCycler Real-Time PCR mutation detection kits (Roche Diagnostics, GmbH, Germany).
6.6% of control subjects, and 6.1% of patients with (50% coronary artery narrowing were determined to have the Factor VLeiden heterozygote mutation. 6.6% of control subjects had the Prothrombin G20210A heterozygote mutation, while 7.7% of patients with (50% coronary artery narrowing had this mutation. The OR for Factor VLeiden was 1.52 (CI: 0.240 - 9.602) and for Prothrombin G20210A mutation, the OR was 1.415 (CI: 0.287 - 6.962).
Although both the heterozygote Factor VLeiden and Prothrombin gene mutations were more frequent in patients with CAD than in control subjects, there was no statistical relationship found to exist between coronary artery disease and the Factor VLeiden and Prothrombin G20210A mutations.
PMCID: PMC2615327  PMID: 18452260
Coronary artery disease; Factor VLeiden; prothrombin G20210A gene
3.  Emerging relations between infectious diseases and coronary artery disease and atherosclerosis 
Cardiovascular disease is the leading cause of death in developed countries. The cause is multifactorial. A substantial proportion of patients with coronary artery disease (CAD) do not have traditional risk factors. Infectious diseases may play a role in these cases, or they may intensify the effect of other risk factors. The association of CAD and Chlamydia pneumoniae infection is firmly established, but causality is yet to be proven. The link with other infectious agents or conditions, such as cytomegalovirus, herpes simplex virus, Helicobacter pylori and periodontitis, is more controversial. Cytomegalovirus infection is more strongly linked than native CAD to coronary artery restenosis after angioplasty and to accelerated CAD after cardiac transplantation. However, new data on this topic are appearing in the literature almost every month. The potential for novel therapeutic management of cardiovascular disease and stroke is great if infection is proven to cause or accelerate CAD or atherosclerosis. However, physicians should not "jump the gun" and start using antibiotic therapy prematurely for CAD. The results of large randomized clinical trials in progress will help establish causality and the benefits of antimicrobial therapy in CAD.
PMCID: PMC1232552  PMID: 10920732
4.  Plasma Oxidized Low-Density Lipoprotein Is an Independent Risk Factor in Young Patients with Coronary Artery Disease 
Disease markers  2011;31(5):295-301.
Objectives: Oxidized low-density lipoprotein (ox-LDL) is considered to be a key factor of initiating and accelerating atherosclerosis. The objective of this study was to investigate the role of ox-LDL in young patients with coronary artery disease (CAD).
Methods: 128 consecutive angiographically proven young CAD patients (aged ≤ 55 years) were enrolled, and 132 age-matched non-CAD individuals (coronary angiography normal or negative finding by coronary ultrafast CT) were set as control group. Conventional risk factors (hypertension, dyslipidemia, diabetes mellitus, obesity, smoking) were evaluated in the two groups. Ox-LDL was measured by competitive ELISA. Framingham risk score (FRS) and absolute 10-year CAD events risk were calculated for each individual.
Results: Male sex was more prevalent in group CAD than in control (87.5% vs. 62.1%; P < 0.01). There were significant differences in smoking history (P < 0.01) and triglyeride (TG) and ratio of apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) (both P < 0.05) but no remarkable difference in other conventional risk factors (all P > 0.05) between group CAD and control. Level of ox-LDL was significantly higher in group CAD than in control (P < 0.01). Multivariate logistic regression showed that male sex (OR, 4.54; 95%CI, 1.76–9.77), smoking quantity (OR, 2.78; 95%CI, 1.34–4.25), TG (OR, 1.42; 95%CI, 1.18–2.83), ApoB/ApoA1 (OR, 1.73; 95%CI, 1.32–4.23), and ox-LDL (OR, 2.15; 95%CI, 1.37–6.95) were independently correlated with CAD in young patients. Area under the curve (AUC) of receiver operating characteristic (ROC) curve of TG, ApoB/ApoA1, and ox-LDL was 0.831, 0.866, and 0.935, respectively (P < 0.001).
Conclusions: Ox-LDL is an important independent risk factor for CAD in young patients after adjusting other risk factors such as smoking, TG, and ApoB/ApoA1.
PMCID: PMC3826422  PMID: 22048271
Risk factors; young; coronary artery disease; oxidized low-density lipoprotein
5.  Assessment of the effect of periodontal treatment in patients with coronary artery disease : A pilot survey 
Periodontitis is a chronic inflammatory condition believed to cause a low but long lasting systemic inflammatory reaction which in turn contributes to the development of atherosclerosis. Recent data suggests that around 40% cases of coronary artery disease remain unaccounted despite the identification of the classical risk factors.
To evaluate the efficacy of non surgical periodontal therapy on the levels of serum inflammatory markers in subjects with chronic periodontitis and known coronary artery disease.
Materials and Methods:
Twenty subjects with known coronary artery disease (CAD) were recruited from the Department of Cardiology, CSM Medical University, Lucknow, India, for this study. Periodontal disease was measured through the clinical parameters bleeding on probing (BOP) and probing depth (PD). All subjects received non surgical periodontal therapy that included oral hygiene instructions and meticulous scaling and root planing. Systemic levels of inflammatory markers such as high-sensitivity C reactive proteins (hsCRP), tumor necrosis factor-α (TNF-α), and white blood cell (WBC) counts were measured prior to and 1 month after periodontal therapy.
Subjects experienced significant reductions in bleeding on probing (BOP) and probing depth (PD), indicating improvement in overall periodontal health. In all subjects, high-sensitivity C reactive proteins (hsCRP), and WBC counts were reduced significantly,; however, tumor necrosis factor-α (TNF-α) levels showed no statistically significant reduction.
In this study, periodontal treatment resulted in a significant decrease in bleeding on probing (BOP) and probing depth (PD), and this treatment lowered the serum inflammatory markers (hsCRP and WBC counts) in patients with coronary artery disease. This may result in a decreased risk for coronary artery disease in the periodontally treated patients.
PMCID: PMC3354455  PMID: 22629030
Coronary artery disease; high-sensitivity C-reactive protein; periodontitis; tumor necrosis factor-α
6.  The Relation Between Ankle-Brachial Index (ABI) and Coronary Artery Disease Severity and Risk Factors: An Angiographic Study 
ARYA Atherosclerosis  2011;7(2):68-73.
The current study aims to determine the relation between ankle–brachial index (ABI) and angiographic findings and major cardiovascular risk factors in patients with suspected coronary artery diseases (CAD) in Isfahan.
In this cross-sectional descriptive-analytic research, patients with suspected CAD were studied. Characteristics of studied subjects including demographics, familial history, past medical history and atherosclerotic risk factors such as diabetes mellitus, hypertension, hyperlipidemia and smoking were obtained using a standard questionnaire. ABI was measured in all studied patients. ABI≤0.9 (ABI+) was considered as peripheral vessel disease and ABI>0.9 (ABI-) was considered as normal. Then, all studied patients underwent coronary artery angiography. The results of the questionnaire and angiographic findings were compared in ABI+ and ABI- groups. Data were analyzed by SPSS 15 using ANOVA, t-test, Spearman's rank correlation coefficient, and discriminant analysis.
In this study, 125 patients were investigated. ABI≤0.9 was seen in 25 patients (20%). The prevalence of ABI+ among men and women was 25.9% and 7.5%, respectively (P=0.01). The prevalence of atherosclerotic risk factors was significantly higher in ABI+ patients than in ABI- ones (P<0.05). ABI+ patients had more significant stenosis than ABI- ones. The mean of occlusion was significantly higher in ABI+ patients with left main artery (LMA), right coronary artery (RCA), left anterior descending artery (LAD), diagonal artery 1 (D1) and left circumflex artery (LCX) involvements (P<0.05).
The findings of this research indicated that ABI could be a useful method in assessing both the atherosclerotic risk factors and the degree of coronary involvements in suspected patients. However, in order to make more accurate decisions for using this method in diagnosing and preventing CAD, we should plan further studies in large sample sizes of general population.
PMCID: PMC3347847  PMID: 22577449
Ankle–Brachial Index; Angiography; Atherosclerotic Risk Factors.
7.  Impact of Metabolic Syndrome and Its Individual Components on the Presence and Severity of Angiographic Coronary Artery Disease 
Yonsei Medical Journal  2010;51(5):676-682.
Metabolic syndrome (MS) has been reported as a potential risk factor of coronary artery disease (CAD). The aims of this study were to assess whether there was a relationship between MS score and CAD angiographic severity, and to assess the predictive value of individual components of MS for CAD.
Materials and Methods
We retrospectively enrolled 632 patients who underwent coronary angiography for suspected CAD (394 men, 61.0 ± 10.6 years of age). MS was defined by the National Cholesterol Education Program criteria with the waist criterion modified into a body mass index (BMI) of more than 25 kg/m2. The MS score defined as the number of MS components. CAD was defined as > 50% luminal diameter stenosis of at least one major epicardial coronary artery. CAD angiographic severity was evaluated with a Gensini scoring system.
Of the patients, 497 (78.6%) had CAD and 283 (44.8%) were diagnosed with MS. The MS score was significantly related to the Gensini score. High fasting blood glucose (FBG) was the only predictive factor for CAD. A cluster including high FBG, high blood pressure (BP), and low high-density lipoprotein cholesterol (HDL-C) showed the highest CAD risk.
The MS score correlates with the angiographic severity of CAD. The predictive ability of MS for CAD was carried almost completely by high FBG, and individual traits with high BP and low HDL-C may act synergistically as risk factors for CAD.
PMCID: PMC2908873  PMID: 20635441
Metabolic syndrome; coronary artery disease; coronary angiography
8.  Usefulness of Cardiovascular Magnetic Resonance Imaging of the Superficial Femoral Artery for Screening Patients with Diabetes Mellitus for Atherosclerosis 
Cardiovascular magnetic resonance (CMR) of the superficial femoral artery (SFA) allows direct visualization of atherosclerotic plaque burden noninvasively. We examined atherosclerosis in 3 groups of patients without a history or symptoms of peripheral arterial disease (PAD) with varying expected burdens: those with diabetes mellitus (DM) and known coronary artery disease (CAD)(n=24); DM and a high prevalence of CAD risk factors (n=20); and controls of similar age without DM or CAD and few CAD risk factors (n=15). We also assessed the diagnostic accuracy of this technique to differentiate between these 3 groups. T1-weighted spin-echo images were used to measure the mean wall thickness (WT) and total wall volume indexed to total vessel volume (IWV). Diagnostic accuracy was assessed by area under the receiver operating characteristic (ROC) curve analysis. Individuals with DM+risk factors and DM+CAD had higher mean WT (1.28mm and 1.37mm) and mean IWV (0.53 and 0.56) compared with controls (mean WT 1.16mm and mean IWV 0.45), all p<0.010. Both mean WT and IWV showed good diagnostic accuracy in discriminating controls from those with DM+CAD (AUCs of 0.85 and 0.87 with p<0.001, respectively), while only IWV discriminated DM+risk factors from controls (AUC=0.82, p<0.001). Neither could discriminate between DM+risk factors and DM+CAD. In conclusion, patients with DM+risk factors and DM+CAD had significantly higher atherosclerotic burden in the SFA on CMR than controls of similar age, with good diagnostic accuracy in differentiating these groups. The high reproducibility and reliability of CMR of the SFA may facilitate improved assessment of atherosclerosis prevalence as well as progression/regression in studies of novel therapies.
PMCID: PMC3377855  PMID: 22459304
therosclerosis; cardiovascular magnetic resonance; diabetes mellitus
9.  Subclinical coronary atherosclerosis identified by coronary computed tomographic angiography in asymptomatic morbidly obese patients 
Heart International  2010;5(2):e15.
Obesity is a common public health problem and obese individuals in particular have a disproportionate incidence of acute coronary events. This study was undertaken to identify coronary artery lesions as well as associated clinical features, risk factors and demographics in patients with a body mass index (BMI) >40 kg/m2 without known coronary artery disease (CAD). Morbidly obese subjects were prospectively recruited to undergo coronary computed tomographic angiography (CCTA) using a dual-source computed tomography (CT) system. CAD was defined as the presence of any atherosclerotic lesion in any one coronary artery segment. The presence, location, and severity of atherosclerosis were related to patient characteristics. Forty-one patients (28 women, mean age, 50.4±10.0 years, mean BMI, 43.8±4.8 kg/m2) served as the study population. Of these, 25 patients (61%) had at least one coronary stenosis. All but 2 patients within the CAD cohort had coronary artery calcium (CAC) scores >0, and most plaques identified (75.4%) were non-calcified. There was a predilection of calcified and non-calcified atherosclerosis involving the left anterior descending (LAD) coronary artery compared with other coronary segments. Univariate predictors of CAD included older age, dyslipidemia, and diabetes. In this preliminary study of young morbidly obese patients, CCTA detected a high prevalence of calcified and non-calcified CAD, although the later predominated.
PMCID: PMC3184688  PMID: 21977300
computed tomography; morbid obesity; risk factors; atherosclerosis.
10.  Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies 
Lancet  2011;377(9763):383-392.
We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis.
We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12 393) with those who did not (controls, n=7383). To identify loci that predispose to myocardial infarction, we compared patients who had angiographic CAD and myocardial infarction (n=5783) with those who had angiographic CAD but no myocardial infarction (n=3644).
In the comparison of patients with angiographic CAD versus controls, we identified a novel locus, ADAMTS7 (p=4·98×10−13). In the comparison of patients with angiographic CAD who had myocardial infarction versus those with angiographic CAD but no myocardial infarction, we identified a novel association at the ABO locus (p=7·62×10−9). The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction.
Our findings indicate that specific genetic predispositions promote the development of coronary atherosclerosis whereas others lead to myocardial infarction in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalised risk assessment and used in the development of novel therapies for CAD.
The PennCath and MedStar studies were supported by the Cardiovascular Institute of the University of Pennsylvania, by the MedStar Health Research Institute at Washington Hospital Center and by a research grant from GlaxoSmithKline. The funding and support for the other cohorts contributing to the paper are described in the webappendix.
PMCID: PMC3297116  PMID: 21239051
11.  The association of ABO blood groups with extent of coronary atherosclerosis in Croatian patients suffering from chronic coronary artery disease 
Biochemia Medica  2013;23(3):351-359.
The aim of study was to: 1) examine the relationship between ABO blood groups and extent of coronary atherosclerosis in patients with chronic coronary artery disease (CAD), 2) compare ABO blood groups distribution in CAD patients and general population, 3) examine possible differences in traditional risk factors frequency in CAD patients with different ABO blood groups.
Materials and methods:
In the 646 chronic CAD patients (72.4% males) coronary angiograms were scored by quantitative assessment using multiple angiographic scoring system, Traditional risk factors were self reported or measured by standard methods. ABO blood distribution of patients was compared with group of 651 healthy blood donors (74.6% males).
Among all ABO blood group patients there was no significant difference between the extent of coronary atherosclerosis with regard to all the three scoring systems: number of affected coronary arteries (P = 0.857), Gensini score (P = 0.818), and number of segments narrowed > 50% (P = 0.781). There was no significant difference in ABO blood group distribution between CAD patients and healthy blood donors. Among CAD patients, men with blood group AB were significantly younger than their pairs with non-AB blood groups (P = 0.008). Among CAD patients with AB blood group, males < 50 yrs were significantly overrepresented when compared with the non-AB groups (P = 0.003).
No association between ABO blood groups and the extent of coronary atherosclerosis in Croatian CAD patients is observed. Observation that AB blood group might possibly identify Croatian males at risk to develop the premature CAD has to be tested in larger cohort of patients.
PMCID: PMC3900083  PMID: 24266306
ABO blood groups; atherosclerosis; coronary artery disease
12.  Rheumatoid arthritis is an independent risk factor for multi-vessel coronary artery disease: a case control study 
Arthritis Research & Therapy  2005;7(5):R984-R991.
The risk for cardiovascular (CV) disease is increased in rheumatoid arthritis (RA) but data on the burden of coronary atherosclerosis in patients with RA are lacking. We conducted a retrospective case-control study of Olmsted County (MN, USA) residents with RA and new-onset coronary artery disease (CAD) (n = 75) in comparison with age-and sex-matched controls with newly diagnosed CAD (n = 128). Angiographic scores of the first coronary angiogram and data on CV risk factors and CV events on follow-up were obtained by chart abstraction. Patients with RA were more likely to have multi-vessel coronary involvement at first coronary angiogram compared with controls (P = 0.002). Risk factors for CAD including diabetes, hypertension, hyperlipidemia, and smoking history were not significantly different in the two cohorts. RA remained a significant risk factor for multi-vessel disease after adjustment for age, sex and history of hyperlipidemia. The overall rate of CV events was similar in RA patients and controls; however, there was a trend for increased CV death in patients with RA. In a nested cohort of patients with RA and CAD (n = 27), we measured levels of pro-inflammatory CD4+CD28null T cells by flow cytometry. These T cells have been previously implicated in the pathogenesis of CAD and RA. Indeed, CD4+CD28null T cells were significantly higher in patients with CAD and co-existent RA than in controls with stable angina (P = 0.001) and reached levels found in patients with acute coronary syndromes. Patients with RA are at increased risk for multi-vessel CAD, although the risk of CV events was not increased in our study population. Expansion of CD4+CD28null T cells in these patients may contribute to the progression of atherosclerosis.
PMCID: PMC1257428  PMID: 16207339
13.  Hepatocyte growth factor in patients with coronary artery disease and its relation to periodontal condition 
Results in Immunology  2011;2:7-12.
Hepatocyte growth factor (HGF) is an angiogenic, cardioprotective factor important for tissue and vascular repair. High levels of HGF are associated with chronic inflammatory diseases, such as coronary artery disease (CAD) and periodontitis, and are suggested as a marker of the ongoing atherosclerotic event in patients with CAD. Periodontal disease is more prevalent among patients with CAD than among healthy people. Recent studies indicate a reduced biological activity of HGF in different chronic inflammatory conditions. Biologically active HGF has high affinity to heparan sulfate proteoglycan (HSPG) on cell-membrane and extracellular matrix. The aim of the study was to investigate the serum concentration and the biological activity of HGF with ELISA and surface plasmon resonance (SPR), respectively, before and at various time points after percutaneous coronary intervention (PCI) in patients with CAD, and to examine the relationship with periodontal condition. The periodontal status of the CAD patients was examined, and the presence of P. gingivalis in periodontal pockets was analyzed with PCR. The HGF concentration was significantly higher, at all time-points, in patients with CAD compared to the age-matched controls (P< 0.001), but was independent of periodontal status. The HGF concentration and the affinity to HSPG adversely fluctuated over time, and the biological activity increased one month after intervention in patients without periodontitis. We conclude that elevated concentration of HGF but with reduced biological activity might indicate a chronic inflammatory profile in patients with CAD and periodontitis.
► We examine the concentration and the biological activity of HGF in patients with CAD, and the relation to periodontal condition. ► Higher serum HGF concentration before and up to one year after percutaneous coronary intervention. ► HGF concentration fluctuated adversely to the HGF biological activity. ► Slightly reduced HGF biological activity in groups with periodontitis and P. gingivalis.
PMCID: PMC3862344  PMID: 24371561
Hepatocyte growth factor; Coronary artery disease; Angiography; Periodontal disease; Porphyromonas gingivalis
14.  Matrix Metalloproteinase 13 Genotype in rs640198 Polymorphism Is Associated with Severe Coronary Artery Disease 
Disease markers  2012;33(1):43-49.
Atherosclerosis as a main etiopathogenetic source for coronary artery disease (CAD) development is intimately related to dynamic changes in the extracellular matrix (ECM). Elevated levels of MMP-13 have been observed in human atherosclerotic plaques which could also involve variability in MMP-13 gene. The aim of the study was to associate rs640198 polymorphism with CAD and/or with its severity.
The study comprised 1071 consecutive patients with suspected or known coronary artery disease (CAD), confirmed by coronary angiography.
Genotyping for the rs640198 polymorphism in MMP-13 gene was performed using Taqman® assay. The TT and TG genotypes of rs640198 polymorphism in MMP-13 gene confer the significantly increased risk of triple vessel disease compared to patients without atherosclerotic lesions in coronary arteries (odds ratio = 1.64, Pcorr = 0.05). Furthermore, an increased risk of having 5 and more stenoses (odds ratio = 1.90, Pcorr = 0.004) was observed in TT and TG carriers (sensitivity of 0.613 and a specificity of 0.544; power of the test is 0.87).
The T allele of MMP-13 intron polymorphism rs640198 is associated with the severity of coronary artery disease, represented by the number of affected arteries as well as by the number of stenoses confirmed by coronarography.
PMCID: PMC3810700  PMID: 22710868
MMP-13; CAD; rs640198; severity
15.  Plasma osteopontin levels are elevated in non-ST-segment elevation acute coronary syndromes. 
BACKGROUND: The regions of ruptured atherosclerotic plaques have numerous macrophages. Osteopontin that modulates macrophage function has been shown in atherosclerotic plaques. We aimed to study the plasma levels of osteopontin in patients with unstable angina or non-ST-seg ment elevation myocardial infarction (NSTEMI) and the rela tionship between osteopontin and the extent of the coronary artery disease (CAD). METHODS: We studied 65 patients with unstable angina or NSTEMI, 25 patients with stable angina and 18 patients as the control group. The extent of coronary artery stenosis was determined by the number of vessels with >50% stenosis. Plasma osteopontin concentrations were measured from the blood samples that were drawn immediately after admission to the emergency department in unstable angina/NSTEMI patients and before the coronary angiograph in the stable angina and control groups. RESULTS: The plasma osteopontin concentration was (495 118 ng/ml) significantly higher in the patients with unstable angina/NSTEMI compared to the stable angina group (319 106 ng/ml) and control group (125+/-54 ng/ml) (p=0.0001 The plasma osteopontin levels were lower in the patients with stable angina pectoris who had one-vessel disease compared to those with two-vessel disease (p=0.01). How ever, in the unstable angina/NSTEMI group, the plasma osteopontin levels were statistically not different among the patients with one-vessel, and two-vessel and three-vessel disease (p=NS). There was no correlation between the plasma osteopontin levels and the extent of coronary stenosis. CONCLUSIONS: The plasma osteopontin levels are elevatedin patients with unstable angina/NSTEMI, but there appears to be no correlation with the extent of CAD. These results ma suggest that osteopontin may have a role in the pathobiology of ACS.
PMCID: PMC2569782  PMID: 17128682
16.  Significance of Small Dense Low-Density Lipoprotein as a Risk Factor for Coronary Artery Disease and Acute Coronary Syndrome 
Yonsei Medical Journal  2006;47(3):405-414.
Small dense LDL (sd-LDL) has recently emerged as an important coronary artery disease (CAD) risk factor. This study was performed to investigate how LDL particle size is related to CAD and acute coronary syndrome (ACS). Blood samples were collected from 504 patients that underwent coronary angiography to evaluate chest pain. The LDL particle size of these samples was measured. The mean LDL particle size was smaller in patients with angiographically proven CAD than in the controls (26.41 ± 0.95 vs 26.73 ± 0.64 nm, p < 0.001), and was negatively correlated with the Framingham risk score (r = -0.121, p = 0.007). Patients with more extensive CAD had smaller LDL particles. LDL particle size was also smaller in patients with acute coronary syndrome as compared to non-ACS patients (26.09 ± 1.42 vs 26.54 ± 0.63 nm, p = 0.011). These results suggest that sd-LDL is independently associated with the incidence and extent of CAD, and can be a risk factor for the development of ACS in the Korean population.
PMCID: PMC2688162  PMID: 16807992
Small dense LDL; coronary artery disease
17.  Association Between Serum Homocysteine Concentration with Coronary Artery Disease in Iranian Patients 
ARYA Atherosclerosis  2011;7(2):63-67.
The role of novel biomarkers like homocystein as a risk factor of coronary artery disease (CAD) is being increasingly recognized. Since there is a marked geographical variation in plasma homocystein concentration and because of importance of hyperhomocysteinemia as a CAD risk factor and due to the paucity of studies in Iran evaluating this risk factor in our population, we evaluated the association between plasma total homocysteine (tHcy) concentration and CAD risk in Iranian population.
In a case-control study, we compared the level of tHcy of forty five patients of angiographically proven CAD with forty five subjects without CAD as control group matched for age and gender. The patients with diabetes, hypertension, thyroid dysfunction, chronic renal failure, hyperlipidemia and obesity and other conventional CAD risk factors were excluded from the study. Plasma tHcy was measured using immunoturbidimetry. The results were compared between groups using student t test.
CAD patients had significantly higher mean plasma tHcy than control group (17.1±5.3 versus 14.2±3.8, P= 0.004).
This study denoted that high plasma homocysteine concentration was associated to CAD risk in Iranian people.
PMCID: PMC3347846  PMID: 22577448
Coronary Artery Disease; Homocysteine.
18.  Deficiency of mast cells in coronary artery endarterectomy of male patients with type 2 diabetes 
Type 2 diabetes is an important risk factor for the development of coronary artery disease (CAD). Focal or diffuse inflammation is often present in the vessels of patients with CAD. Mast cells are frequently present in the plaques as well as in the inflammatory infiltrates in the atherosclerotic vessel wall. In the study we wanted to examine whether there are differences in the morphology, number and distribution of mast cells and in their ability to modify the atherosclerotic process in coronary arteries (CA) in the diabetic vs. the hypertensive population of patients with CAD.
Coronary artery endarterectomy specimens were obtained from patients with diabetes or hypertension as the only risk factor for CAD. The specimens were stained with haematoxylin-eosin and Sulphated Alcian Blue for mast cells and with immunofluorescent methods for fibrinogen-fibrin and IgG deposits in the vessel wall. Both morphological and stereological assessments were conducted for mast cells and mononuclear cell infiltrates.
The histological analysis of the vessel wall of diabetic patients in comparison with hypertensive patients showed a damaged endothelial cells layer and deposits of fibrin-fibrinogen and IgG in the tunica intima and media. The stereological count revealed a diminished numerical density of mast cells and a significantly higher volume density of the mononuclear cells. Mast cells displayed cytoplasmic vacuolization, extracellular extrusion of granule and pyknotic nuclei.
This preliminary study suggests that the impaired mast cells might be the reason for more extensive inflammatory and immunologic atherosclerotic changes in the CA vessel wall of CAD patients with type 2 diabetes.
Trial registration
PMCID: PMC3112392  PMID: 21569588
19.  Coronary angiographic scoring systems: an evaluation of their equivalence and validity 
American heart journal  2012;164(4):547-552.e1.
Structured Abstract
Multiple scoring systems have been devised to quantify angiographic coronary artery disease (CAD) burden, but it is unclear how these scores relate to each other and which scores are most accurate. The aim of this study was to compare coronary angiographic scoring systems 1) with each other and 2) with intravascular ultrasound (IVUS) derived plaque burden in a population undergoing angiographic evaluation for CAD.
Coronary angiographic data from 3600 patients was scored using 10 commonly used angiographic scoring systems and inter-score correlations were calculated. In a subset of 50 patients, plaque burden and plaque area in the left anterior descending coronary artery was quantified using IVUS and correlated with angiographic scores.
All angiographic scores correlated with each other (range for Spearman coefficient (ρ): 0.79-0.98, p<0.0001); the two most widely used scores, Gensini and CASS-70, had a ρ = 0.90, p<0.0001. All scores correlated significantly with average plaque burden and plaque area by IVUS (range ρ: 0.56-0.78, p<0.0001 and 0.43-0.62, p<0.01, respectively). The CASS-50 score had the strongest correlation (ρ: 0.78 and 0.62, p<0.0001) and the Duke Jeopardy score the weakest correlation (ρ: 0.56 and 0.43, p<0.01) with plaque burden and area, respectively.
Angiographic scoring systems are strongly correlated with each other and with atherosclerotic plaque burden. Scoring systems therefore appear to be a valid estimate of CAD plaque burden.
PMCID: PMC3913177  PMID: 23067913
Atherosclerosis; Angiography; Coronary Disease; Intravascular Ultrasound; Scoring Systems
20.  Single Nucleotide Polymorphisms of TCF7L2 Are Linked to Diabetic Coronary Atherosclerosis 
PLoS ONE  2011;6(3):e17978.
Coronary artery disease (CAD) shares common risk factors with type 2 diabetes (T2DM). Variations in the transcription factor 7-like 2 (TCF7L2) gene, particularly rs7903146, increase T2DM risk. Potential links between genetic variants of the TCF7L2 locus and coronary atherosclerosis are uncertain. We therefore investigated the association between TCF7L2 polymorphisms and angiographically determined CAD in diabetic and non-diabetic patients.
Methodology/Principal Findings
We genotyped TCF7L2 variants rs7903146, rs12255372, and rs11196205 in a cross-sectional study including 1,650 consecutive patients undergoing coronary angiography for the evaluation of established or suspected stable CAD. Significant CAD was diagnosed in the presence of coronary stenoses ≥50%. Variant rs7903146 in the total study cohort was significantly associated with significant CAD (adjusted additive OR = 1.29 [1.09–1.53]; p = 0.003). This association was strong and significant in T2DM patients (n = 393; OR = 1.91 [1.32–2.75]; p = 0.001) but not in non-diabetic subjects (OR = 1.09 [0.90–1.33]; p = 0.370). The interaction risk allele by T2DM was significant (pinteraction = 0.002), indicating a significantly stronger impact of the polymorphism on CAD in T2DM patients than in non-diabetic subjects. TCF7L2 polymorphisms rs12255372 and rs11196205 were also significantly associated with CAD in diabetic patients (adjusted additive OR = 1.90 [1.31–2.74]; p = 0.001 and OR = 1.75 [1.22–2.50]; p = 0.002, respectively). Further, haplotype analysis demonstrated that haplotypes including the rare alleles of all investigated variants were significantly associated with CAD in the whole cohort as well as in diabetic subjects (OR = 1.22 [1.04–1.43]; p = 0.013 and OR = 1.67 [1.19–2.22]; p = 0.003, respectively).
These results suggest that TCF7L2 variants rs7903146 rs12255372, and rs11196205 are significantly associated with angiographically diagnosed CAD, specifically in patients with T2DM. TCF7L2 therefore appears as a genetic link between diabetes and atherosclerosis.
PMCID: PMC3058059  PMID: 21423583
21.  Silent coronary artery disease in type 2 diabetes mellitus: the role of Lipoprotein(a), homocysteine and apo(a) polymorphism 
There is little data on the relationship between novel cardiovascular risk factors and silent coronary artery disease (CAD) in diabetic patients. We investigated whether Lipoprotein(a), homocysteine and apolipoprotein(a) polymorphism are associated with angiographically assessed asymptomatic coronary artery disease (CAD) in diabetic patients.
1,971 type 2 diabetic patients without clinical signs of cardiovascular diseases and with a negative history of CAD were consecutively evaluated. Among them, 179 patients showed electrocardiographic abnormalities suggestive of ischemia or previous asymptomatic myocardial infarction. These 179 patients were subjected to a non-invasive test for CAD (ECG stress testing and/or scintigraphy). Among patients with a highly positive stress testing (n = 19) or a positive scintigraphy (n = 74), 75 showed an angiographically documented CAD (CAD group). Seventy-five patients without CAD (NO CAD group) were matched by age, sex and duration of diabetes to CAD patients. In NO CAD patients an exercise ECG test, a 48-hour ambulatory ECG and a stress echocardiogram were negative for CAD.
Lipoprotein(a) levels (22.0 ± 18.9 versus 16.0 ± 19.4 mg/dl; p < 0.05), homocysteine levels (13.6 ± 6.6 versus 11.4 ± 4.9 mmol/l; p < 0.05) and the percentage of subjects with at least one small apolipoprotein(a) isoform (70.7% versus 29.3%; p < 0.0001) were higher in CAD than NO CAD group. Logistic regression analysis showed that apolipoprotein(a) polymorphism (OR:8.65; 95%CI:3.05–24.55), microalbuminuria (OR:6.16; 95%CI:2.21–17.18), smoking (OR:2.53; 95%CI:1.05–6.08), HDL (OR:3.16; 95%CI:1.28–7.81), homocysteine (OR:2.25; 95%CI:1.14–4.43) and Lipoprotein(a) (OR:2.62; 95%CI:1.01–6.79) were independent predictors of asymptomatic CAD.
The present investigation shows an independent association of Lipoprotein(a), homocysteine and apo(a) polymorphism with silent CAD. Other studies are needed to establish whether these parameters are suitable for CAD screening in diabetic patients.
PMCID: PMC149426  PMID: 12473160
22.  Increased prevalence of subclinical coronary atherosclerosis detected by coronary computed tomography angiography in HIV-infected men 
AIDS (London, England)  2010;24(2):243-253.
The degree of subclinical coronary atherosclerosis in HIV-infected patients is unknown. We investigated the degree of subclinical atherosclerosis and the relationship of traditional and nontraditional risk factors to early atherosclerotic disease using coronary computed tomography angiography.
Design and methods
Seventy-eight HIV-infected men (age 46.5 ± 6.5 years and duration of HIV 13.5 ± 6.1 years, CD4 T lymphocytes 523 ± 282; 81% undetectable viral load), and 32 HIV-negative men (age 45.4 ± 7.2 years) with similar demographic and coronary artery disease (CAD) risk factors, without history or symptoms of CAD, were prospectively recruited. 64-slice multidetector row computed tomography coronary angiography was performed to determine prevalence of coronary atherosclerosis, coronary stenosis, and quantitative plaque burden.
HIV-infected men demonstrated higher prevalence of coronary atherosclerosis than non-HIV-infected men (59 vs. 34%; P = 0.02), higher coronary plaque volume [55.9 (0–207.7); median (IQR) vs. 0 (0–80.5) μl; P = 0.02], greater number of coronary segments with plaque [1 (0–3) vs. 0 (0–1) segments; P = 0.03], and higher prevalence of Agatston calcium score more than 0 (46 vs. 25%, P = 0.04), despite similar Framingham 10-year risk for myocardial infarction, family history of CAD, and smoking status. Among HIV-infected patients, Framingham score, total cholesterol, low-density lipoprotein, CD4/CD8 ratio, and monocyte chemoattractant protein 1 were significantly associated with plaque burden. Duration of HIV infection was significantly associated with plaque volume (P = 0.002) and segments with plaque (P = 0.0009) and these relationships remained significant after adjustment for age, traditional risk factors, or duration of antiretroviral therapy. A total of 6.5% (95% confidence interval 2–15%) of our study population demonstrated angiographic evidence of obstructive CAD (>70% luminal narrowing) as compared with 0% in controls.
Young, asymptomatic, HIV-infected men with long-standing HIV disease demonstrate an increased prevalence and degree of coronary atherosclerosis compared with non-HIV-infected patients. Both traditional and nontraditional risk factors contribute to atherosclerotic disease in HIV-infected patients.
PMCID: PMC3154841  PMID: 19996940
atherosclerosis; cardiovascular risk factors; coronary artery disease; coronary computed tomography angiography; HIV
23.  Serum protein profiles predict coronary artery disease in symptomatic patients referred for coronary angiography 
BMC Medicine  2012;10:157.
More than a million diagnostic cardiac catheterizations are performed annually in the US for evaluation of coronary artery anatomy and the presence of atherosclerosis. Nearly half of these patients have no significant coronary lesions or do not require mechanical or surgical revascularization. Consequently, the ability to rule out clinically significant coronary artery disease (CAD) using low cost, low risk tests of serum biomarkers in even a small percentage of patients with normal coronary arteries could be highly beneficial.
Serum from 359 symptomatic subjects referred for catheterization was interrogated for proteins involved in atherogenesis, atherosclerosis, and plaque vulnerability. Coronary angiography classified 150 patients without flow-limiting CAD who did not require percutaneous intervention (PCI) while 209 required coronary revascularization (stents, angioplasty, or coronary artery bypass graft surgery). Continuous variables were compared across the two patient groups for each analyte including calculation of false discovery rate (FDR ≤ 1%) and Q value (P value for statistical significance adjusted to ≤ 0.01).
Significant differences were detected in circulating proteins from patients requiring revascularization including increased apolipoprotein B100 (APO-B100), C-reactive protein (CRP), fibrinogen, vascular cell adhesion molecule 1 (VCAM-1), myeloperoxidase (MPO), resistin, osteopontin, interleukin (IL)-1β, IL-6, IL-10 and N-terminal fragment protein precursor brain natriuretic peptide (NT-pBNP) and decreased apolipoprotein A1 (APO-A1). Biomarker classification signatures comprising up to 5 analytes were identified using a tunable scoring function trained against 239 samples and validated with 120 additional samples. A total of 14 overlapping signatures classified patients without significant coronary disease (38% to 59% specificity) while maintaining 95% sensitivity for patients requiring revascularization. Osteopontin (14 times) and resistin (10 times) were most frequently represented among these diagnostic signatures. The most efficacious protein signature in validation studies comprised osteopontin (OPN), resistin, matrix metalloproteinase 7 (MMP7) and interferon γ (IFNγ) as a four-marker panel while the addition of either CRP or adiponectin (ACRP-30) yielded comparable results in five protein signatures.
Proteins in the serum of CAD patients predominantly reflected (1) a positive acute phase, inflammatory response and (2) alterations in lipid metabolism, transport, peroxidation and accumulation. There were surprisingly few indicators of growth factor activation or extracellular matrix remodeling in the serum of CAD patients except for elevated OPN. These data suggest that many symptomatic patients without significant CAD could be identified by a targeted multiplex serum protein test without cardiac catheterization thereby eliminating exposure to ionizing radiation and decreasing the economic burden of angiographic testing for these patients.
PMCID: PMC3566965  PMID: 23216991
atherosclerosis; biomarkers; cardiac catheterization; coronary angiography; coronary stenosis; multiplex proteomics
24.  Cytomegalovirus Localization in Atherosclerotic Plaques is Associated with Acute Coronary Syndromes: Report of 105 Patients 
It has been shown that cytomegalovirus (CMV) is present in coronary atherosclerotic plaques, but the clinical rele-vance of this presence remains to be elucidated. In this study we sought to examine CMV infection in atherosclerosis patients defined by different methods and to identify the clinical significance of CMV replication in the atherosclerotic plaques. The study included 105 consecutive patients who were admitted to our department and underwent coronary artery bypass grafting (CABG) surgical interventions. Coronary atherosclerotic specimens as well as 53 specimens from the mamillary artery of these same patients were analyzed. Enzyme-linked immunosorbent assay (ELISA) and poly-merase chain reaction (PCR) methods were used for evaluations. The CMV PCR test result was positive for 28 (26.7%) of patients with coronary artery atherosclerosis. After adjusting for other risk factors, coronary artery disease patients with a history of acute coronary syndrome were more likely to be positive for CMV PCR test (P=0.027; odds ratio: 4.2; 95% CI: 1.18-15.0). They were also more likely to have a positive family history for cardiovascular diseases (CVD). This study confirms previous evidence about the replication of CMV virus in the atherosclerotic plaques of coronary arteries and brings clinical significance to this observation by showing a higher prevalence of acute coronary syndromes in those patients with CMV-infected plaques. Our study also suggests a familial vulnerability to CMV replication in the coronary artery walls.
PMCID: PMC3405798  PMID: 22891128
cytomegalovirus; atherosclerotic plaques; acute coronary syndrome; enzyme-linked immunosorbent assay; ELISA
25.  Vitamin K-Antagonists Accelerate Atherosclerotic Calcification and Induce a Vulnerable Plaque Phenotype 
PLoS ONE  2012;7(8):e43229.
Vitamin K-antagonists (VKA) are treatment of choice and standard care for patients with venous thrombosis and thromboembolic risk. In experimental animal models as well as humans, VKA have been shown to promote medial elastocalcinosis. As vascular calcification is considered an independent risk factor for plaque instability, we here investigated the effect of VKA on coronary calcification in patients and on calcification of atherosclerotic plaques in the ApoE−/− model of atherosclerosis.
Methodology/Principal Findings
A total of 266 patients (133 VKA users and 133 gender and Framingham Risk Score matched non-VKA users) underwent 64-slice MDCT to assess the degree of coronary artery disease (CAD). VKA-users developed significantly more calcified coronary plaques as compared to non-VKA users. ApoE−/− mice (10 weeks) received a Western type diet (WTD) for 12 weeks, after which mice were fed a WTD supplemented with vitamin K1 (VK1, 1.5 mg/g) or vitamin K1 and warfarin (VK1&W; 1.5 mg/g & 3.0 mg/g) for 1 or 4 weeks, after which mice were sacrificed. Warfarin significantly increased frequency and extent of vascular calcification. Also, plaque calcification comprised microcalcification of the intimal layer. Furthermore, warfarin treatment decreased plaque expression of calcification regulatory protein carboxylated matrix Gla-protein, increased apoptosis and, surprisingly outward plaque remodeling, without affecting overall plaque burden.
VKA use is associated with coronary artery plaque calcification in patients with suspected CAD and causes changes in plaque morphology with features of plaque vulnerability in ApoE−/− mice. Our findings underscore the need for alternative anticoagulants that do not interfere with the vitamin K cycle.
PMCID: PMC3430691  PMID: 22952653

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